Alzheimer’s disease immunotherapy

A novel use of immune checkpoint blockade approach

The importance of the choroid plexus (CP) in the crosstalk between the CNS and the immune system, has suggested that the way this interface is functioning might be critical to the ability of the CNS to cope with neurodegenerative conditions [1, 2]. Studying CP function in animal models of chronic neurodegenerative diseases, Amyotrophic lateral sclerosis (ALS) [3] and Alzheimer's disease (AD) [4], we observed that disease progression is associated with local suppression of CP activity in supporting immune cell trafficking to the CNS. Under these conditions, we showed that breaking systemic immune tolerance, either by active vaccination approaches [3] or by targeting regulatory T cells (Tregs) [4], can augmented CP-gateway activity for leukocyte trafficking. The activation of this immune-brain axis was followed by accumulation of immunoregulatory cells at cerebral sites of pathology, and in the case of AD transgenic mice, was associated with amyloid-β plaque clearance and mitigation of cognitive decline. Conversely, augmenting systemic immune suppression in AD mice was associated with accelerated disease pathology. Collectively, these findings suggested that in chronic neurodegenerative diseases, systemic immune suppression interferes with the activity of the CP in orchestrating recruitment of leukocytes to the CNS, needed for coping with disease-escalating factors within the brain and with tissue remodeling.

Therapeutic potential of PD-1 immune checkpoint blockade in Alzheimer’s disease

The fact that transient reduction of systemic Tregs was sufficient to drive a cascade of immune response that led to modification of AD pathology is reminiscent of the situation in Tregs in cancer, in which these cells hinder the ability of the immune system to mount an effective anti-tumor response. Therefore, we considered an alternative approach for reducing systemic immunosuppression, by adopting the use of an immune checkpoint blockade, which has revolutionized cancer therapy in recent years. Specifically, we found that in AD animal models, treatment with immune checkpoint blockade that targets the Programmed cell death protein 1 (PD-1) pathway, drives a systemic immune response that leads to activation of the CP for leukocyte trafficking, and culminates in reversing disease pathology [5]. These findings could be considered as a gamechanger in fighting AD and potentially other neurodegenerative diseases: the research field of neurodegenerative diseases in general, and Alzheimer’s disease in particular, was dominated for the last two decades by clinical attempts to arrest the neuroinflammatory response by administration of immune-suppressive and anti-inflammatory drugs; these attempts have generally failed. Our findings suggest that in order to fight neuroinflammation under chronic neurodegenerative conditions, systemic immunity should be boosted, rather than suppressed. Additionally, these findings introduces the idea that to fight AD it might be possible to target the immune system rather than directly target specific disease escalating factors within the brain. Such an approach, by the virtue of the ability of recruited immune cells to display multiple functions, provides a comprehensive therapy, and is likely to be applicable to the diverse forms of AD and perhaps other neurodegenerative diseases.

References

  1. Schwartz M, Baruch K. The resolution of neuroinflammation in neurodegeneration: leukocyte recruitment via the choroid plexus. The EMBO journal, 2014;33:7-22.
  2. Schwartz M, Baruch K. Breaking peripheral immune tolerance to CNS antigens in neurodegenerative diseases: boosting autoimmunity to fight-off chronic neuroinflammation. Journal of autoimmunity, 2014;54:8-14.
  3. Kunis G, Baruch K, Miller O, Schwartz M. Immunization with a myelin-derived antigen activates the brain's choroid plexus for recruitment of immunoregulatory cells to the CNS and attenuates disease progression in a mouse model of ALS. The Journal of neuroscience : the official journal of the Society for Neuroscience, 2015;35:6381-93.
  4. Baruch K, Rosenzweig N, Kertser A, Deczkowska A, Sharif AM, Spinrad A et al. Breaking immune tolerance by targeting Foxp3(+) regulatory T cells mitigates Alzheimer's disease pathology. Nature Communications, 2015;6:7967.
  5. Baruch K, Deczkowska A, Rosenzweig N, Tsitsou-Kampeli A, Sharif AM et al. PD-1 immune checkpoint blockade reduces pathology and improves memory in mouse models of Alzheimer's disease. Nature Medicine, 2016;22: 135–7.